The addition of vericiguat to sacubitril/valsartan improved the composite endpoint. Add a finishing touch on heart failure medical therapy by vericiguat as secret ingredient

Several studies have reported that the Fantastic Four, a standard combination of heart failure medications, is associated with better prognosis.1 Therefore, patients with heart failure with reduced ejection fraction (HFrEF) are recommended to be treated with this combination regimen whenever possible.2 Furthermore, the European Society of Cardiology and the American Heart Association/American College of Cardiology guidelines recommend vericiguat as having classified as Class IIb recommendation in HFrEF,3, 4 and there are high expectations for a five-drug combination therapy including vericiguat.5 Furthermore, the Japanese Circulation Society recently recommended vericiguat as Level IIa in the recommendation and evidence level for the treatment of HFrEF in the 2025 revised heart failure clinical practice guidelines.6 Patients with heart failure show reduced sensitivity of soluble guanylate cyclase (sGC) to nitric oxide (NO).7 Vericiguat increases cyclic guanosine monophosphate (cGMP) by enhancing the sensitivity of sGC to NO. Vericiguat directly stimulates sGC, promoting cGMP production and acting on vascular smooth muscle and cardiac myocytes (the cGMP-protein kinase G PKG pathway) without relying on NO.7, 8 This cGMP–PKG pathway is used not only by vericiguat, but also by sacubitril/valsartan. Is there any clinical significance in addition of vericiguat to sacubitril/valsartan? This study evaluated the efficacy of an addition of vericiguat to sacubitril/valsartan, focusing on clinical outcomes. This retrospective study included patients who had received sacubitril/valsartan or vericiguat between May 2021 and May 2024. Safety analyses were performed for all patients. Efficacy analyses were performed for patients who were able to continue receiving sacubitril/valsartan and vericiguat, and were followed up. Comparisons were performed among three groups: a group treated with vericiguat and other heart failure medications (mineralocorticoid receptor antagonists MRA, sodium–glucose co-transporter 2 SGLT2 inhibitors, and beta-blockers) without sacubitril/valsartan (vericiguat group), a group treated with sacubitril/valsartan and other heart failure medications without vericiguat (sacubitril/valsartan group), and a group treated with sacubitril/valsartan and other heart failure medications, to which vericiguat was added subsequently (add vericiguat group). Patients who self-withdrew, those who had discontinued sacubitril/valsartan or vericiguat at other departments or institutions, those with dementia or difficulties in obtaining family support and could not continue administering their medications, and those on dialysis were excluded. This study was conducted in accordance with the Declaration of Helsinki and approved in advance by the Ethics Review Committee (Ethics Review Committee No. 2023–43). Owing to the retrospective and opt-out nature of this study, informed consent was obtained from all patients. Patients were excluded if they were not on dialysis or had a preserved left ventricular ejection fraction (LVEF ≥50%). Guideline-based dosing was administered at the discretion of the treating cardiologist, and sacubitril/valsartan or vericiguat was initiated during outpatient care or initial hospitalization for heart failure. Sacubitril/valsartan was titrated to the target dose (100–400 mg). Vericiguat was also initiated at 2.5 mg and titrated to a target dose of 10 mg every 1 or 3 months. For both sacubitril/valsartan and vericiguat, the dose was reduced or titration was delayed if patients experienced symptoms of hypotension such as dizziness or lightheadedness. Baseline characteristics, including laboratory, echocardiographic, and medication data, were collected from the participants. Echocardiographic data were measured by an experienced certified echocardiographer (Japan Society of Echocardiography), independently of the attending physician. LVEF and stroke volume were assessed using two-dimensional echocardiography. Statistical analyses were performed using JMP software (version 9.0; SAS Institute Inc., Cary, NC, USA). Continuous variables were checked for normality, and analysis of variance or Student's t-test was used if variances were equal, while the Wilcoxon rank-sum test was used if variances were non-normal or unequal. Categorical data (e.g. 0/1 variables) were analysed using the chi-square test or Fisher's exact test. Tukey's honest significant difference test was used for post hoc analysis of the three groups. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for time-course prognosis and cardiovascular events. Statistically significance was set at p < 0.05 in bilateral tests. Thirty-five patients received vericiguat plus other heart failure medications except sacubitril/valsartan (4 of 39 patients withdrew) (vericiguat group), and 127 patients received sacubitril/valsartan plus other heart failure medications (7 of 134 patients withdrew), of whom 81 patients continued treatment with sacubitril/valsartan alone (sacubitril/valsartan group). Forty-two patients (4 of 46 patients withdrew) received vericiguat in addition to sacubitril/valsartan (add vericiguat group). We assessed clinical characteristics in 158 patients with heart failure who were not on dialysis and did not meet the criteria for heart failure with preserved ejection fraction (HFpEF). These characteristics included age, sex, body mass index (BMI), comorbidities such as coronary artery disease, chronic atrial fibrillation, diabetes mellitus, and hypertension (HT), as well as LVEF, New York Heart Association (NYHA) functional class, log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (log10 NT-proBNP), haemoglobin, estimated glomerular filtration rate, the number of prior hospitalizations for heart failure, and the duration of the observation period. The distribution of NYHA functional class was as follows: class I in 18 patients (11%), class II in 65 (41%), class III in 58 (37%), and class IV in 17 (11%). The median age was 77 (71–83), 78 (71–85), and 75 years (69–82) in the vericiguat, sacubitril/valsartan, and add vericiguat groups, respectively, with no significant differences (p = 0.33). The observation period from the initiation of sacubitril/valsartan or vericiguat administration was 455 days (376–599) in the vericiguat group, 761 days (446–893) in the sacubitril/valsartan group, and 726 days (447–842) in the add vericiguat group. Significant differences were observed among the three groups in BMI, HT, and Log10 NT-proBNP (pg/ml) (BMI, p = 0.02; HT, p = 0.002; and Log10 NT-proBNP, p < 0.001). Dose reduction or discontinuation of sacubitril/valsartan or vericiguat was based on the discretion of the attending physician, depending on blood pressure and subjective symptoms. The rates of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sacubitril/valsartan, SGLT2 inhibitors, and MRAs in the vericiguat group, as well as the median simple guideline-directed medical therapy scores,2 were 54%, 80%, 57%, 0%, 66%, 69%, and 5 points, respectively. In the sacubitril/valsartan group, these values were 52%, 85%, 0%, 100%, 56%, 63%, and 7 points, respectively. Whereas, in the add vericiguat group, these values were 29%, 100%, 0%, 100%, 76%, 79%, and 8 points, respectively. We analysed the prognosis of three items: (1) composite endpoint (combination of cardiovascular death, emergency hospitalization due to heart failure, and emergency consultation due to heart failure), (2) cardiovascular death, and (3) all-cause death. In the Cox proportional hazard model, HT, BMI, Log10 NT-proBNP, and treatment groups (vericiguat, sacubitril/valsartan, and add vericiguat groups) were used as covariates. The add vericiguat group showed no significant difference in cardiovascular death and all-cause mortality compared to the sacubitril/valsartan group (cardiovascular death: HR 1.12, 95% CI 0.26–4.18, p = 0.80; total death: HR 0.68, 95% CI 0.15–2.13, p = 0.54). However, the add vericiguat group showed a trend toward a significantly lower risk of the composite endpoint compared to the sacubitril/valsartan group (HR 0.34, 95% CI 0.12–0.82, p = 0.01). This trend was also observed between the add vericiguat group and the vericiguat group, suggesting the superiority of the add vericiguat. These results suggest that the addition of vericiguat to sacubitril/valsartan-based therapy may enhance its preventive effect against cardiovascular events and acute heart failure-related exacerbations. Furthermore, for individual endpoints, such as cardiovascular death and all-cause mortality, the add vericiguat group showed the best results, and a consistent trend toward reduced risk was observed compared to the vericiguat and sacubitril/valsartan groups (Figure 1). These findings suggest that additional therapy synergistically suppresses disease progression and prevents acute exacerbations. This study showed a significant reduction in the risk of the composite endpoint, consisting of cardiovascular death, emergency hospitalization for heart failure, and emergency medical visits, in the add vericiguat group than in the sacubitril/valsartan group, However, there was no significant difference in the risk of cardiovascular death or all-cause death alone. Interestingly, this result is similar to the results of the VICTORIA trial, in which the vericiguat group had significantly reduced primary endpoints of heart failure hospitalization and cardiovascular death compared with the placebo group; however, no significant differences were observed for cardiovascular death alone or all-cause mortality.9 Based on the results of the VICTORIA trial, Chew et al.10 stated that a reduction in the composite endpoint of cardiovascular death and heart failure hospitalization contributed to an increase in the quality-adjusted life years (QALY). In the present study, the composite endpoints of emergency hospitalization due to heart failure and emergency visit due to worsening heart failure more sensitively reflected the effect of administering vericiguat, likely due to the high frequency of these events and the high statistical power of the analysis. In other words, the early administration of vericiguat along with sacubitril/valsartan may have had a more significant impact on non-fatal events such as emergency visit and emergency hospitalization due to worsening heart failure rather than on the final outcome of death. In future, it is expected that the addition of vericiguat to sacubitril/valsartan and other heart failure medications will positively affect QALYs in non-HFpEF patients having an LVEF of <50%, and not just those with an LVEF of <45%, similar to the VICTORIA trial. Furthermore, regardless of whether the patient has HErEF or HFpEF, heart failure at stage C or later is known to result in repeated hospitalizations, and more frequent hospitalizations for heart failure have been associated with worse prognosis.11 Although vericiguat did not significantly reduce mortality during the observation period, it is possible that it primarily acted by slowing the progression of heart failure and thereby preventing non-fatal events. These findings highlight the potential importance of initiating vericiguat therapy at an earlier stage of heart failure, such as stage B, before clinical symptoms become evident.12 The prognostic significance of the add vericiguat or sacubitril/valsartan groups over the vericiguat group for the composite endpoint of cardiovascular death and all-cause death indicates that sacubitril/valsartan should be considered for the treatment of non-HFpEF patients. Furthermore, regarding cardiovascular death and all-cause mortality, the number of events was small, and sample size limitations may have prevented the detection of significant differences. However, the effects on non-fatal events may ultimately show statistical significance in cardiovascular death and all-cause mortality in long-term observations. This study has several limitations. First, this was a retrospective observational study conducted at a single institution with a relatively small sample size of 158 patients. Second, the observation period varied owing to differences in the timing of drug initiation. Furthermore, the analysis was limited to patients who were able to continue administering sacubitril/valsartan and vericiguat and excluded those who discontinued the medication, those whose prescriptions were terminated at other hospitals, or those for whom continuing medication was difficult due to factors such as cognitive decline. Therefore, the results of the analysis should be generalized with caution. Future analyses, including the impact of continued medication, are required with longer observation periods and larger sample sizes. In conclusion, this study clearly shows that the additional therapy of vericiguat to sacubitril/valsartan is effective in suppressing serious clinical outcomes in patients with non-HFpEF. Therefore, the significance of the additional therapy of vericiguat to sacubitril/valsartan should be evaluated in future. The authors acknowledge Akita Tomoyuki, MD, PhD, Department of Epidemiology and Infectious Disease Control, Graduate School of Biomedical Sciences, Hiroshima University for analysis. The authors acknowledge Ms. Yoshimi Shitakubo, Department of Clinical Research Department, NHO Kure Medical Center for analysis. The authors acknowledge Ms. Aya Ohshita, medical administrative assistant, NHO Kure Medical Center for data acquisition. The authors would like to thank Editage (www.editage.jp) for English language editing. Conflict of interest: none declared.